Consoli David C, Brady Lillian J, Bowman Aaron B, Calipari Erin S, Harrison Fiona E
Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Pharmacology, Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN, USA.
J Neurochem. 2021 May;157(3):656-665. doi: 10.1111/jnc.15151. Epub 2020 Sep 21.
Dopamine (DA) has important roles in learning, memory, and motivational processes and is highly susceptible to oxidation. In addition to dementia, Alzheimer's disease (AD) patients frequently exhibit decreased motivation, anhedonia, and sleep disorders, suggesting deficits in dopaminergic neurotransmission. Vitamin C (ascorbate, ASC) is a critical antioxidant in the brain and is often depleted in AD patients as a result of disease-related oxidative stress and dietary deficiencies. To probe the effects of ASC deficiency and AD pathology on the DAergic system, gulo mice, which like humans depend on dietary ASC to maintain adequate tissue levels, were crossed with APP/PSEN1 mice and provided sufficient or depleted ASC supplementation from weaning until 12 months of age. Ex vivo fast-scan cyclic voltammetry showed that chronic ASC depletion and APP/PSEN1 genotype both independently decreased dopamine release in the nucleus accumbens, a hub for motivational behavior and reward, while DA clearance was similar across all groups. In striatal tissue containing nucleus accumbens, low ASC treatment led to decreased levels of DA and its metabolites 3,4-dihydroxyohenyl-acetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA). Decreased enzyme activity observed through lower pTH/TH ratio was driven by a cumulative effect of ASC depletion and APP/PSEN1 genotype. Together the data show that deficits in dopaminergic neurotransmission resulting from age and disease status are magnified in conditions of low ASC which decrease DA availability during synaptic transmission. Such deficits may contribute to the non-cognitive behavioral changes observed in AD including decreased motivation, anhedonia, and sleep disorders.
多巴胺（DA）在学习、记忆和动机过程中发挥着重要作用，且极易被氧化。除痴呆症外，阿尔茨海默病（AD）患者常表现出动机减退、快感缺乏和睡眠障碍，提示多巴胺能神经传递存在缺陷。维生素C（抗坏血酸盐，ASC）是大脑中的一种关键抗氧化剂，由于疾病相关的氧化应激和饮食缺乏，AD患者体内的维生素C常常耗竭。为探究ASC缺乏和AD病理对多巴胺能系统的影响，将像人类一样依赖饮食中的ASC来维持足够组织水平的古洛糖酸内酯氧化酶基因敲除小鼠（gulo小鼠）与APP/PSEN1小鼠杂交，并从断奶至12月龄给予充足或缺乏ASC的补充剂。体外快速扫描循环伏安法显示，长期的ASC缺乏和APP/PSEN1基因型均独立降低了伏隔核中的多巴胺释放，伏隔核是动机行为和奖赏的中枢，而所有组的多巴胺清除率相似。在含有伏隔核的纹状体组织中，低ASC处理导致多巴胺及其代谢产物3,4-二羟基苯乙酸（DOPAC）、3-甲氧基酪胺（3-MT）和高香草酸（HVA）的水平降低。通过较低的磷酸化酪氨酸羟化酶/酪氨酸羟化酶（pTH/TH）比值观察到的酶活性降低是由ASC缺乏和APP/PSEN1基因型的累积效应驱动的。这些数据共同表明，在低ASC条件下，年龄和疾病状态导致的多巴胺能神经传递缺陷会被放大，低ASC会在突触传递过程中降低多巴胺的可用性。这种缺陷可能导致AD患者出现非认知行为改变，包括动机减退、快感缺乏和睡眠障碍。
